Anti-carious chewing gums, candies, gels, toothpastes and dentifrices

ABSTRACT

The invention relates to anticarious delivery vehicles, specifically chewing gums, candies, confectioneries, toothpastes, dentifrices and gels. The invention specifically provides chewing gums, candies, confectioneries, toothpastes, dentifrices and gels containing non-toxic sparingly soluble calcium and phosphate compounds as additives, causing the release of calcium and phosphate ions into the oral cavity gradually and persistently for a period no less than 5 minutes. The invention provides released calcium phosphate ions that diffuse into partially demineralized tooth enamel or dentin, leading to remineralization and repair of caries lesions, dental plaque, open dentinal tubules and exposed dentin. The invention thus provides agents and methods for remineralization of teeth and for reducing or eradicating cariogenic challenge in plaque following sucrose intake. The formulations of the invention can thereby produce effective anticaries actions without the use of fluoride. In addition, the formulations of the invention can be used to desensitize hypersensitive teeth.

This invention was made during research activities that were supportedin part by Grants DE05354 and DE10840 from the NIDR to the ADAHF andcarried out at the National Institute of Standards and Technology. TheGovernment may have certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention comprises the use of non-toxic sparingly soluble calciumand phosphate compounds as additives to chewing gums, candies,confectioneries, gels, toothpastes or dentifrices that cause the releaseof calcium and phosphate ions into the oral cavity gradually andpersistently for an appropriate and therapeutically useful period. Thereleased calcium phosphate ions can diffuse into partially demineralizedtooth enamel or dentin, leading to remineralization and repair of thecaries lesion. The released calcium phosphate ions can also diffuse intodental plaque to cause remineralization of teeth and to reduce oreradicate cariogenic challenge in plaque following sucrose intake. Thus,these formulations can produce effective anticaries actions without theuse of fluoride. The released calcium phosphate ions can also causeprecipitation of calcium phosphate minerals inside open dentinal tubulesand on exposed dentine surfaces to desensitize hypersensitive teeth.These agents will have minimal adverse effects and require little efforton the part of the user.

2. Summary of the Related Art

Chewing gums have the potential of being an effective vehicle fordelivering therapeutic agents to teeth because they permit protractedcontact of the agent to the teeth with minimal effort on the part of apatient. Despite the recognized desirability of chewing gums as vehiclesfor delivering anticarious agents to teeth, no effective embodiments ofanticarious chewing gums have been developed in the art.

The effectiveness of prior attempts at using potential anticariousagents in chewing gums was reviewed by Edgar and Geddes (1990, Br. Dent.J. 24: 173-176). For example, dicalcium phosphate dihydrate (DCPD;CaHPO₄.2H₂ O), was used at a dose of 7.5 wt % and assessed for itseffects on the calcium (Ca) and phosphate (PO₄) concentrations in saliva(Pickel and Bilotti, 1965, J. Alabama Med. Soc. 2: 286-287). A chewinggum containing 10 wt % DCPD was assessed for anticarious effects in twodifferent clinical studies (Finn and Jamison, 1967, J. Amer. Dent.Assoc. 74: 987-995; Richardson et al., 1972, J. Canad. Dent. Assoc. 6:213-218). The results from the Richardson study showed that, althoughsugar-DCPD gum produced a lower caries score than did the gum containingsugar alone, the cariogenicity of the sugar-DCPD gum was equivalent tothat of sugar-free gum. The marginal degree of effectiveness of DCPD asan anticaries gum additive in this study was accepted in the art asdemonstrating that DCPD was ineffective as an anticarious agent. As aresult of this study, there has been little interest or activity in theart in using calcium phosphate-containing gums as anticarious agents.

Recently, the feasibility of using two new calcium phosphate additivesin bubble gum has been evaluated for effectiveness in increasingsalivary mineral saturation levels and/or enhancing salivation (Chow etal., 1994, J. Dent. Res. 73: 26-32). In these in vivo studies,monocalcium phosphate monohydrate (MCPM; Ca(H₂ PO₄)₂ .H₂ O) and anequimolar mixture of dicalcium phosphate anhydrous (DCPA; CaHPO₄) andtetracalcium phosphate (TTCP; Ca₄ (PO₄)₂ O were used as chewing gumadditives. These studies showed that both the MCPM and DCPA/TTCP gumsincreased the calcium and phosphate concentrations in saliva during achewing period of 16 minutes. The extent of increase was much greaterthan those produced by gums containing DCPD. The degree of saturationwith respect to tooth mineral was significantly increased by bothexperimental gums, with the greater increase being produced by theDCPA/TTCP gum.

U.S. Pat. Nos. 5,037,639, 5,268,167, 5,427,768, and 5,437,857, issued toTung, disclose and claim the use of amorphous calcium phosphate (Ca₃(PO₄)₂) and derivatives as chewing gum additives for toothremineralization. However, evidence that ACP chewing gums actuallyremineralize teeth was not disclosed.

While some of the above additives have had some efficacy under someconditions, shortcomings have been associated with each. The DCPA/TTCPmixture requires an extensive preparation process: TTCP must be preparedin a furnace at a high temperature (1500° C.) and then blended withcommercially-available DCPA after each calcium phosphate salt has beenground to the desired particle size. ACP compounds must be precipitatedin aqueous systems, thereby having variable composition and relativelyundefined particles size. Also, the stability of ACP in gum base or agel is likely to be limited, and a stabilizer may be required to achievethe desired shelf life.

Other calcium-containing compounds have been studied for theireffectiveness in remineralization of teeth in situ. U.S. Pat. No.5,378,131 to Greenberg disclosed the use of calcium glycerophosphate asa chewing gum additive for dental health benefits. This patent alsodisclosed the use of several other calcium compounds, including calciumlactate and calcium gluconate, to achieve an anticaries effect when usedas a chewing gum additive. However, chewing gums containing calciumcompounds as additives can only raise calcium concentration levels insaliva. In fact, phosphate concentration levels would be expected to bedecreased as a result of chewing calcium-containing gums, based on theshowing that saliva phosphate levels decrease with increased salivationstimulated by gum chewing (Chow et al., ibid.). Thus, thesecalcium-containing chewing gums disclosed by Greenberg are cariostatic,rather than anticarious. There is thus a need in the art for vehiclesthat release phosphate ions into the oral cavity in conjunction withincreased calcium ion concentration to provide an anticaries effects notfound in the gums known in the prior art.

In contrast to the recognized desirability of chewing gum as a vehiclefor delivery of anticarious agents, candies have not been generallyrecognized as a means for delivering calcium and phosphate ions into theoral environment. A major reason for this is that sugar, the majoringredient of candies, is the chief culprit of dental caries. With theadvent of sugar-free candies (i.e., candies that do not containsignificant amount of fermentable carbohydrates), however, candies canbe an effective means of delivering therapeutic agents for dentalcaries.

SUMMARY OF THE INVENTION

This invention provides chewing gums, sugar-free candies andconfectioneries, gels, toothpastes and dentrifrices that are formulatedto release calcium and phosphate ions into the mouth of a human patient.

In a first aspect, the invention provides a calcium phosphate-containingcomposition comprising an acidic chewing gum and further comprises asparingly-soluble calcium phosphate salt. In a most preferredembodiment, the calcium phosphate salt is α-tricalcium phosphate. Inother preferred embodiments, the calcium phosphate salt is dicalciumphosphate anhydrous, dicalcium phosphate dihydrate, octacalciumphosphate or tetracalcium phosphate. Preferably, the sparingly-solublecalcium phosphate salt comprises from about 0.5 to about 10 percent ofthe gum formulation by weight (weight percent, or wt%). More preferably,the sparingly-soluble calcium phosphate salt comprises from about 1 toabout 5 wt % of the gum formulation. In the chewing gums of theinvention, the sparingly-soluble calcium phosphate salts are providedwith a particle size of less than about 50 μm, and more preferablyhaving a particle size of from about 1 to about 20 μm.

In a second aspect, the invention provides a calciumphosphate-containing chewing gum that comprises a calcium compound and aphosphate salt. In a preferred embodiment, the gum is an acidic gum. Inanother preferred embodiment, the gum is a neutral gum. In yet otherpreferred embodiments, the calcium compound is a sparingly-solublecalcium compound. In such embodiments, the sparingly-soluble calciumcompound is a calcium salt of glycerophosphate, lactate, gluconate, orfumarate. In other embodiments, the calcium compound is a solublecompound, and is preferably calcium acetate or calcium chloride. Inthese embodiments, the gum is formulated to slow the release of calciumions from the soluble calcium compound so that calcium ions are releasedover a 5 to 15 minute period.

Preferably, the gums provided in this second aspect of the invention areformulated to contain calcium compounds at from about 0.5 to 10 weightpercent of the chewing gum. More preferably, the calcium compoundscomprise from about 1 to about 5 weight percent of these chewing gums.Additionally, the calcium compounds provided in the gums of this aspectof the invention are provided having a particle size of less than 50 μm,more preferably from about 1 to about 20 μm.

The gums of this aspect of the invention are also formulated to containa phosphate salt. Preferred phosphate salts include but are not limitedto Na₂ HPO₄, NaH₂ PO₄, and Ca(H₂ PO₄)₂.H₂ O. Preferably, the gums inthis aspect of the invention are formulated to contain phosphate saltsat from about 0.5 to 10 weight percent of the chewing gum. Morepreferably, the phosphate salts comprise from about 1 to about 5 weightpercent of these chewing gums. Additionally, the phosphate saltsprovided in the gums of this aspect of the invention are provided havinga particle size of less than 50 μm, more preferably from about 1 toabout 20 μm.

In a third aspect, the invention provides a calcium phosphate-containingcomposition comprising a candy or confectionery and further comprising acalcium phosphate salt. In preferred embodiments, the candy orconfectionary is sugar-free. In a most preferred embodiment, the calciumphosphate salt is α-tricalcium phosphate. In other preferredembodiments, the calcium phosphate salt is β-tricalcium phosphate,monocalcium phosphate monobasic, dicalcium phosphate anhydrous,dicalcium phosphate dihydrate, octacalcium phosphate, tetracalciumphosphate, and mixtures and combinations thereof. Preferably, thecalcium phosphate salt comprises from about 0.5 to about 10 percent ofthe candy formulation by weight (weight percent, or wt%). Morepreferably, the calcium phosphate salt comprises from about 1 to about 5wt % of the candy formulation. In the sugar-free candies of theinvention, the calcium phosphate salts are provided with a particle sizeof less than about 50 μm, and more preferably having a particle size offrom about 1 to about 20 μm. Sparingly-soluble calcium phosphate saltsare appropriate but are not required for this embodiment of theinvention, due to the preferred composition of the candies andconfectioneries of the invention as described in detail herein. Althoughsugar-free candies and confectionaries are preferred, calciumphosphate-containing embodiments of the candies and confectioneries ofthe invention prepared using sugar (specifically, sucrose) are withinthe scope of the invention. In such embodiments, it will be recognizedthat the cariostatic and remineralizing benefits of the calciumphosphate components of the inventive candies and confectioneries willoutweigh the cariogenic propensity of sugar.

In a fourth aspect, the invention provides a calciumphosphate-containing candy or confectionery that comprises a calciumcompound and a phosphate salt. In preferred embodiments, the candy orconfectionary is sugar-free. In preferred embodiments, the calciumcompound is a sparingly-soluble calcium salt of glycerophosphate,lactate, gluconate, or fumarate. In other preferred embodiments, thecalcium compound is a soluble compound, and is preferably calciumacetate or calcium chloride. In these embodiments, the candy isformulated to slow the release of calcium ions from the soluble calciumcompound so that calcium ions are released over a 5 to 15 minute period.

Preferably, the candies provided in this aspect of the invention areformulated to contain calcium compounds at from about 0.5 to 10 weightpercent of the candy. More preferably, the calcium compounds comprisefrom about 1 to about 5 weight percent of these candies. Additionally,the calcium compounds provided in the candies of this aspect of theinvention are provided having a particle size of less than 50 μm, morepreferably from about 1 to about 20 μm.

The candies of this aspect of the invention are also formulated tocontain a phosphate salt. Preferred phosphate salts include but are notlimited to Na₂ HPO₄, NaH₂ PO₄, and Ca(H₂ PO₄)₂.H₂ O. Preferably, thecandies in this aspect of the invention are formulated to containphosphate salts at from about 0.5 to 10 weight percent. More preferably,the phosphate salts comprise from about 1 to about 5 weight percent ofthese candies. Additionally, the phosphate salts provided in the candiesof this aspect of the invention are provided having a particle size ofless than 50 μm, more preferably from about 1 to about 20 μm.

Although sugar-free candies and confectionaries are preferred, calciumphosphate-containing embodiments of the candies and confectionaries ofthe invention prepared using sugar (specifically, sucrose) are withinthe scope of this aspect of the invention.

In a fifth aspect the invention provides a calcium phosphate-containingremineralizing gel that comprises a calcium phosphate compound selectedfrom the group consisting of α-tricalcium phosphate, tetracalciumphosphate and monocalcium phosphate monohydrate. Certain of thesecalcium phosphate-containing embodiments of the invention are providedas a dry mixture of the calcium phosphate compound and, optionally,other components of the gel, to be reconstituted into a gel by theaddition of water or other liquid containing advantageous additives(such as flavorings, etc.) immediately before use. In other embodimentsof this aspect of the invention are provided a combination of a gelcomprising a sparingly-soluble calcium compound and a gel comprising aphosphate salt. In a preferred embodiment, the gel is carboxymethylcellulose or hydroxypropyl methylcellulose. In another preferredembodiments, the sparingly-soluble calcium compound is a calcium salt ofglycerophosphate, lactate, gluconate, or fumarate.

Preferably, the gels provided in this aspect of the invention areformulated to contain sparingly-soluble calcium compounds at from about0.5 to 10 weight percent of the gel. More preferably, thesparingly-soluble calcium compounds comprise from about 1 to about 5weight percent of these gels. Additionally, the sparingly-solublecalcium compounds provided in the gels of this aspect of the inventionare provided having a particle size of less than 50 μm, more preferablyfrom about 1 to about 20 μm.

Combination gel embodiments of this aspect of the invention are alsoformulated to contain a gel comprising a phosphate salt. Preferredphosphate salts include but are not limited to Na₂ HPO₄, NaH₂ PO₄, andCa(H₂ PO₄)₂.H₂ O. Preferably, the remineralizing gels in this aspect ofthe invention are formulated to contain phosphate salts at from about0.5 to 10 weight percent of the gel. More preferably, the phosphatesalts comprise from about 1 to about 5 weight percent of these gels.Additionally, the phosphate salts provided in the gels of this aspect ofthe invention are provided having a particle size of less than 50 μm,more preferably from about 1 to about 20 μm.

In preferred embodiments, the gels of the invention are provided whereineach of the calcium-containing and phosphate-containing gels areformulated and kept separate until immediately before use. For use, thegels are mixed and applied to teeth, including the occlusal, proximal,cervical and smooth surfaces of teeth. Remineralization of toothmaterial as provided by the invention is accomplished by allowing thegels of the invention to remain in contact with the tooth surfaces for aperiod from about 5 minutes to about 12 hours or overnight. Highmolecular weight crystal growth inhibitors, including the gelling agentscomprising the gels, are also included in the gels of the invention.Fluoride ion can also advantageous ly be added to such gels.

In a sixth aspect the invention provides a calcium phosphate-containingtoothpaste or dentifrice. In preferred embodiments, the toothpastes anddentifrices of this aspect of the invention comprise a calcium phosphatesalt selected from the group consisting of α-tricalcium phosphate,tetracalcium phosphate and monocalcium phosphate monohydrate. Certain ofthese calcium phosphate-containing embodiments of the invention areprovided as a dry mixture of the calcium phosphate compound and,optionally, other components of the gel, to be reconstituted into a gelby the addition of water or other liquid containing advantageousadditives (such as flavorings, etc.) immediately before use. Inadditional preferred embodiments, the dentrifrices and toothpastes ofthe invention comprise a combination of two dentifrice pastes, onedentifrice paste comprising a sparingly-soluble calcium compound andanother dentifrice paste comprising a phosphate salt. In addition to thesparingly-soluble calcium and phosphate components of these dentifrices,the inventive dentifrices also comprise active ingredients such asfluoride compounds as well as conventional components of dentifrices. Inpreferred embodiments, the sparingly-soluble calcium compound is acalcium salt of glycerophosphate, lactate, gluconate, or fumarate.

Preferably, the toothpastes and dentifrices provided in this aspect ofthe invention are formulated to contain calcium phosphate salts orsparingly-soluble calcium compounds at from about 0.5 to 10 weightpercent of the toothpaste or dentifrice. More preferably, thesparingly-soluble calcium compounds comprise from about 1 to about 5weight percent of these toothpastes and dentifrices. Additionally, thesparingly-soluble calcium compounds provided in the toothpastes anddentifrices of this aspect of the invention are provided having aparticle size of less than 50 μm, more preferably from about 1 to about20 μm.

Embodiments of the toothpastes and dentifrices of this aspect of theinvention formulated as combinations are also formulated to contain atoothpaste or dentifrice comprising a phosphate salt. Preferredphosphate salts include but are not limited to Na₂ HPO₄, NaH₂ PO₄, andCa(H₂ PO₄)₂.H₂ O. Preferably, the toothpastes and dentifrices in thisaspect of the invention are formulated to contain phosphate salts atfrom about 0.5 to 10 weight percent. More preferably, the phosphatesalts comprise from about 1 to about 5 weight percent. Additionally, thephosphate salts provided in the toothpastes and dentifrices of thisaspect of the invention are provided having a particle size of less than50 μm, more preferably from about 1 to about 20 μm.

The toothpastes and dentifrices of the invention are provided whereineach of the sparingly-soluble calcium-containing andphosphate-containing dentifrices are formulated and kept separate untilimmediately before use. For use, the toothpastes and dentifrices aremixed and applied to teeth, including the occlusal, proximal, cervicaland smooth surfaces of teeth. Remineralization of tooth material asprovided by the invention is accomplished by allowing the toothpastesand dentifrices of the invention to remain in contact with the toothsurfaces for about 1 to about 5 minutes. Fluoride ion can alsoadvantageously be added to such toothpastes and dentifrices. Alsoadvantageously included in the toothpastes and dentifrices of theinvention are macromolecular crystal growth inhibitors, preferablycellulose compounds and most preferably carboxymethyl cellulose, oralternatively sodium and potassium pyrophosphate.

The invention also provides methods for remineralizing teeth to reduceor eliminate dental caries and other dental disease. The methods of theinvention are provided wherein a human patient simply chews the gums,candies or confectioneries of the invention, uses the toothpastes ordentifrices, or applies the gels of the invention to release calcium andphosphate ions into the mouth and onto teeth. In a preferred embodiment,the gum is chewed, candy or confectionery is chewed or used as alozenge, the toothpaste or dentifrice is used, or the gel is applied,from about one to about five minutes, more preferably from about threeto about ten minutes, and most preferably from about five to aboutfifteen or twenty minutes, to effect the release of calcium andphosphate ions into the mouth and in contact with teeth. In preferredembodiments, the gels of the invention are applied and allowed to remainin contact with teeth for about 8 hours or overnight.

A preferred use for the methods of this invention is for remineralizinga dental lesion in a human. Another preferred use for the methods of theinvention is for remineralizing dental plaque in a human. Yet anotherpreferred use for the methods of this invention is for reducingcariogenic challenge to human teeth. The methods of the invention arealso preferably used for desensitizing hypersensitive human teeth, andfor remineralizing open dentinal tubules and exposed dentine surfaces inhuman teeth.

Certain preferred embodiments of the gums, candies, confectioneries,toothpastes, dentifrices and gels of the invention, as well as usefulmethods for using such embodiments for treating and remineralizingteeth, are described in greater detail in the following sections of thisapplication.

DETAILED DESCRIPTION OF THE INVENTION

It has been known for some time that hydroxyapatite materials have thebasic properties of human bones and teeth. A considerable amount ofresearch has been directed to the remineralization of incipient dentallesions, including plaque deposits, by deposition of hydroxyapatite, Ca₅(PO₄)₃ OH, on such lesions, so that the hydroxyapatite is incorporatedinto the dental structure at the point of lesion.

Remineralization of tooth enamel has been carried out experimentallyboth in vivo and in vitro. These studies have concentrated on theremineralizing properties of saliva and synthetic solutionssupersaturated with respect to hydroxyapatite. Chewing gums, candies andconfectioneries, toothpastes, dentifrices and gels as provided hereinare useful as vehicles for delivering hydroxyapatite-depositing calciumphosphate compositions to teeth in vivo. An advantage of these deliveryvehicles is that calcium phosphates and compounds that release calciumand phosphate ions into the mouth are provided as simple mixtures in thechewing gum, candy, confectionery, toothpaste, dentifrice or gel,because delivery to teeth is effectively achieved simply by having ahuman use the delivery vehicle of the invention (e.g., by chewing thecalcium phosphate-containing gums, candies and confectioneries and usingthe calcium phosphate-containing toothpastes, dentifrices and gels).

Compounds that release calcium and phosphate ion are selected from anumber of commercially-available and other compounds that are recognizedas food additives in other contexts. All such additives encompassed bythe present invention are intended to be non-toxic. For the purpose ofthis invention, the term "non-toxic" is intended to conform withaccepted and established definitions of safety, such as are described bythe designation "generally accepted as safe" by the Food and DrugAdministration. Also encompassed in this definition are those compoundsthat have been added to food for some time and which are recognized assafe under conditions of their intended use. The additives of theinvention, including calcium and phosphate salts should be non-toxicenough for oral use at the intended levels on a regular basis, andstable for the desired shelf life.

Preferred calcium ion-releasing compounds are sparingly solublecalcium-containing salts of biologically-compatible acids and otherbasic calcium compounds, i.e., calcium compounds having a solubilitygreater than about 0.1 % and less than about 10 % under conditions ofneutral pH. Sparingly soluble calcium compounds include but are notlimited to the calcium salts of gluconate, glycerophosphate, lactate,and fumarate, Ca(OH)₂, CaO, monocalcium phosphate, dicalcium phosphateanhydrous, dicalcium phosphate dihydrate, α-tricalcium phosphate,octacalcium phosphate, tetracalcium phosphate, and combinations andmixtures thereof.

There are two major categories of gums useful as components of theinstant invention: neutral pH gums and acidic pH gums. Acidic pH gumsinclude most fruit flavored chewing gums and bubble gums. Neutral pHgums include all mint flavored gums and some other non-fruit flavoredgums. It has been found that none of the calcium phosphate compoundstested (with the exception of monocalcium phosphate monohydrate) wascapable of releasing calcium or phosphate ions unless the gum had anacidic pH and produced an acid pH in saliva (i.e., pH less than 7.0), asshown herein in Table III below. This new finding may explain whydicalcium phosphate dihydrate-containing mint-flavored (neutral pH) gumswere previously reported to show only marginal anti-caries effects (seeFinn and Jamison, 1967, ibid. and Richardson et al., 1972, ibid.). Incontrast, monocalcium phosphate monohydrate (MCPM) was found to becapable of releasing calcium and phosphate ions into saliva fromnon-acidic gums (Table III). However, the acidity of MCPM produces atart taste which may be incompatible with some gum flavors. In addition,MCPM produces an unpleasant after-taste if the gum contain more than 2or 3 % MCPM. Thus, the most useful calcium phosphate-containing gums areacidic pH gums, which represent only a minor portion of the gums beingconsumed.

However, neutral gums have surprising been found to be capable ofreleasing anticarious calcium phosphate agents under certain conditions,specifically, by adding separate calcium-containing andphosphate-containing compounds to the gum. Several non-toxic calciumcompounds are sparingly soluble, and when used as chewing gum additives,allowed calcium ions to be released into saliva gradually andcontinuously (see Table IV). These compounds include the calcium saltsof gluconic acid, lactic acid, fumaric acid, and glycerophosphoric acid.Unlike calcium phosphates, the solubilities of these calcium-containingcompounds are essentially independent of pH, resulting in theseadditives being capable of performing well in both acid and neutral pHgums. In order to obtain significant calcium ion release, the calciumsource should have a solubility that is greater than 0.5% at neutral pH;solubilities of 2% and above are preferred. Preferred calcium salts aresparingly soluble, that is, having a solubility of less than 10 % atneutral pH. Calcium carbonate, and calcium citrate and calcium tartrate(the calcium salts of two commonly-used food acids) are too insoluble toproduce effective release (see Table IV). On the other hand, highlysoluble calcium-continuing compounds such as calcium acetate and calciumchloride are of limited usefulness because these compounds are incapableof sustained release of calcium ions from the chewing gums. (However,soluble calcium compounds may be useful with other delivery vehicles ofthis invention such as candies and confectioneries which take 5 minutesor longer to dissolve.)

The anticaries effects of calcium ion-releasing compounds of theinvention are significantly augmented by adding a non-toxic phosphatesalt as a second additive. Preferred phosphate salts include sodiumphosphate (most preferably comprising an equimolar mixture of Na₂ HPO₄and NaH₂ PO₄, to maintain pH at 7). Addition of sodium phosphate to thecalcium ion-releasing additives of the invention results in the desiredrelease of both calcium and phosphate ions in quantities capable ofdepositing calcium phosphate mineral (including hydroxyapatite) on thesurface of teeth in vivo (see Table IV). In alternative embodiments, asparingly-soluble calcium source can be admixed with a calcium phosphatesalt, such as MCPM, which serves as a source for both calcium andphosphate ions.

Candies and confectioneries of the invention comprise preferablysweeteners such as sorbitol, mannitol, aspartame and saccharine. Sugar(specifically sucrose, fructose, glucose, and combinations thereof)containing candies and confectioneries are also provided by theinvention. Flavorings, such as citrus and other flavorings, that arenaturally acidic are used to provide an advantageous acidic environmentas discussed above. In addition, calcium compounds having substantiallyhigher solubility than those calcium compounds useful in the gums anddentifrices of the invention can be used in the candies andconfectioneries as provided herein; non-limiting examples of suchcalcium compounds are calcium chloride and calcium acetate. Preferredcandies of the invention are non-chewable hard candies. Preferably,particles of the calcium and phosphate compounds comprising the candiesand confectioneries of the invention are uniformly distributedthroughout the candy or confectionery. In preferred embodiments, thecandies and confectioneries of the invention are formulated whereincalcium and phosphate ions are released from the candies andconfectioneries as they dissolve. It will be understood that the releaserate of the calcium and phosphate ions depends on the concentration anddistribution of these ions in the candies and confectioneries and on therate of dissolution of the candies and confectioneries, which in turn isdependent on the surface area of the candy or confectionery and itscomposition. In these formulations, the solubilities of the calcium andphosphate-containing compounds contribute relatively less to the releaserates of calcium and phosphate ions than does the candy or confectionarydissolution rate. Calcium and phosphate ion release kinetics can beformulated accordingly by those of skill in the art based on theseparameters.

Remineralizing gels of the invention comprise a non-toxic gellingcompound as are conventionally used in foods, including but not limitedto agar, geletine, carboxymethyl cellulose, chitin, gum acacia, gumarabic, gum xanthum, hydroxyethyl cellulose and hydroxypropylmethylcellulose. The gels of the invention are formulated to have aneutral pH to avoid irritation of oral tissues upon prolonged exposure.Each gel also comprises sufficient water or other aqueous solution toproduce the desired consistency, as well as high molecular weightcrystal growth inhibitors, and flavoring and coloring agents. Highmolecular weight crystal growth inhibiting agents include the gellingagents themselves, as described above, and also phosphoproteins (such asare disclosed in Ternine & Conn, 1976, Calcif. Tiss. Res. 22: 149-157),polycarboxylates (such as are disclosed in Howie-Meyers et al., 1995, inMineral Scale Formation and Inhibition, Amjad, ed., Plenum Press: NewYork, Ch. 15, pp. 169-182), and polyphosphorylated polyvinyl alcohol (asare described in Shimabayashi et al., 1995, in Mineral Scale Formationand Inhibition, Amjad, ed., Plenum Press: New York, Ch. 14, pp.157-168). Such gels also comprises a sparingly-soluble calcium salt or aphosphate salt as described above for the gums of the invention.

Calcium phosphate-containing gels of the invention are preferablyprovided as a dry powder comprising the calcium phosphate compound and,optionally, dry flavorings, sweeteners, gelling agents, and othercomponents are described above. In these embodiments, the gel isreconstituted by adding water or other liquid comprising advantageousadditives (such as colorings, flavorings, sweeteners, gelling agents,and the like).

Dentifrices and toothpastes of the invention comprise conventionalcomponents of dentifrices and toothpastes, including but not limited tosweeteners such as sorbitol or saccharine, abrasives such as hydratedsilica, foaming agents such as sodium lauryl sulfate, binders such asvarious forms of cellulose or gums, lubricants such as glycerin, pigmentwhiteners such as titanium oxide, food coloring and water.

As with the gels of the invention, the dentifrices and toothpastes ofthe invention are advantageously provided as a dry powder comprising thecalcium phosphate compound and, optionally, dry flavorings, sweeteners,gelling agents, and other components are described above. In theseembodiments, the gel is reconstituted by adding water or other liquidcomprising advantageous additives (such as colorings, flavorings,sweeteners, gelling agents, and the like).

An additive of particular significance in dental applications isfluoride containing compounds. In toothpaste and gel embodiments of thisinvention, fluoride salts such as NaF, CaF₂, SnF₂, Na₂ PO₃ F or Na₂ SiF₆are added in sufficient quantity they increase the rate of formation ofHA and fluorapatite. Preferably, embodiments of the invention will havea fluoride content of about 200 to 2200 ppm. The total amount offluoride released during use of the toothpastes gels of this inventionis 0.05 to 10 mg.

Using the chewing gums of the invention, sustained release of calciumand phosphate ions from the gums, candies and other delivery vehicles ofthe invention should be maintained for at least about 3-5 minutes andpreferably, at least about 3-10 minutes and most preferably, at leastabout 3-15 minutes.

The following Examples are intended to further illustrate certainpreferred embodiments of the invention and are not limiting in nature.

EXAMPLES Preparation of calcium phosphate-containing gums

Calcium phosphate-containing gums were prepared as follows. Calciumlactate, calcium gluconate, calcium glycerophosphate, monocalciumphosphate monobasic, disodium hydrogen phosphate, and sodium dihydrogenphosphate were all obtained commercially as food grade chemicals.α-tricalcium phosphate (α-TCP) was prepared by heating a mixturecontaining 2 moles of commercially-available DCPA and 1 mole ofcommercially available calcium carbonate (CaCO₃) to 1200° C. for 6 h.Gums used were LifeSaver® peppermint gum (as a neutral pH gum) orLifeSavers® grape flavored bubble gum (as an acidic pH gum).Experimental gums were prepared by uniformly dispersing the calciumphosphate additive into the control gums.

Release of calcium and phosphate ions from the gum into saliva

The ability of calcium phosphate-containing chewing gums of theinvention to release calcium and phosphate ions into the mouth uponchewing by a subject was determined as follows. Three human subjectswith normal salivary flow (≧0.2 mL saliva per minute) chewed gums withor without various formulations of calcium phosphate for between 0-16minutes. Saliva samples were collected at intervals of either 0-2minutes or 14-16 minutes. Calcium ion concentration in the salivasamples were determined using a calcium electrode (Orion; see Vogel etal., 1987, J. Dent. Res. 66: 1691-1697). Phosphate ion concentration insaliva were determined by spectrophotometry (Vogel et al., ibid.).

The results of these studies are shown in Table I below. The data inTable I show the effect on salivary calcium ion concentration in salivareleased after chewing an acidic pH gum containing 1 to 5 wt % α-TCP waschewed. Calcium ion release from the 5% α-TCP gum was statisticallyequivalent to that of the 5% (DCPA/TTCP) gum.

                  TABLE I                                                         ______________________________________                                        Release of Ca into Saliva from Acid pH Gums Containing                        Various Calcium Phosphate Additives                                                        Calcium Concentration.sup.#, mmol/L                              Additive       0-2 min.   14-16 min                                           ______________________________________                                        control        0.41 ± 0.27                                                                           0.80 ± 0.30                                      5% (TTCP/DCPA) 10.08 ± 1.72                                                                          1.29 ± 0.10                                      5% α-TCP 9.04 ± 2.03                                                                           1.82 ± 0.59                                      2.5% α-TCP                                                                             4.27 ± 0.72                                                                           1.81 ± 0.86                                      1% α-TCP 2.71 ± 0.01                                                                           1.02 ± 0.05                                      ______________________________________                                         .sup.# mean ± s.d (n = 3)                                             

Effects of gum chewing on plaque composition

The ability of calcium phosphate-containing chewing gums of theinvention to remineralize plaque upon chewing by a subject wasdetermined as follows. Twelve human subjects with normal salivary flowchewed gums with or without various formulations of calcium phosphate.In these experiments, plaque was allowed to accumulate for 48 h prior toeach experiment. Baseline samples of plaque were collected prior to thebeginning of each experiment, and then subjects rinsed the oral cavitywith a 10% sucrose solution for about 1 min. Subjects then chewedcontrol or experimental gums for between 0-15 minutes. Two pooled plaquesamples from upper and lower molars of each subject were collected 7 and15 min after gum chewing began, with 1 min saliva samples collected justbefore each plaque sample. For each sample, plaque pH was determinedusing microelectrodes (glass pH electrode; Vogel et al., 1990, J. Dent.Res. 69: 1316-1323). In addition, plaque fluid was separated from plaquesolids by centrifugation and acidified with 0.1M perchloric acid toprevent precipitation of calcium phosphate (as the result of increasedcalcium phosphate levels in saliva and removal of dissolved carbonateanion as carbon dioxide from saliva after sample collection). Freecalcium ion concentration in the saliva samples were determined using acalcium electrode as described above. Total calcium and phosphate ionconcentration in saliva were determined by spectrophotometry (asdescribed in Vogel et al., ibid.). Data on salivary and plaque pH, andcalcium and phosphate ion concentrations were used to calculate thedegree of saturation with respect to tooth mineral in plaque.

The results from these experiments are shown in Table II. The data inTable II show that chewing gum containing 2.5% α-TCP producedsignificant increases in the calcium and phosphate ion concentrations inplaque. These increases prevented a decrease in mineral saturation inplaque after sucrose intake and completely eradicated the acidicchallenge produced by sucrose. In contrast, the subject group that usedthe control gum experienced a decreased plaque mineral saturation levelafter the sucrose rinse that was indicative of increased caries risk.

                                      TABLE II                                    __________________________________________________________________________    Plaque Composition After A Sucrose Rinse and Chewing Acidic pH Gums                  pH       Ca!.sub.F                                                                              Ca!.sub.T                                                                              P!.sub.T pIAP                               Time (min)                                                                           Ctrl.sup.1                                                                        Exp.sup.2                                                                         Ctrl                                                                              Exp  Ctrl                                                                              Exp  Ctrl Exp  Ctrl                                                                              Exp                            __________________________________________________________________________    -1     7.08.sup.3                                                                        7.07                                                                              0.77                                                                              0.83 1.87                                                                              1.89 13.1 12.5 48.5                                                                              49.2                                  (.45).sup.3                                                                       (.33)                                                                             (.27)                                                                             (.48)                                                                              (.50)                                                                             (.78)                                                                              (2.6)                                                                              (1.3)                                                                              (1.4)                                                                             (1.6)                          -1 to 0                                                                              SUCROSE CHALLENGE                                                       0 to 15                                                                             GUM CHEWING                                                             7     6.15                                                                              6.50                                                                              1.42                                                                              <3.58.sup.4                                                                        2.69                                                                              <5.82                                                                              8.88 <11.1                                                                              52.7                                                                              >48.8                                 (.42)                                                                             (.48)                                                                             (.50)                                                                             (1.9)                                                                              (.78)                                                                             (2.0)                                                                              (1.2)                                                                              (3.0)                                                                              (2.3)                                                                             (1.9)                          15     6.58                                                                              6.31                                                                              1.33                                                                              <2.51                                                                              2.23                                                                              <3.96                                                                              8.69 9.70 50.4                                                                              >47.8                                 (.50)                                                                             (1.9)                                                                             (.34)                                                                             (1.37)                                                                             (.70)                                                                             (1.53)                                                                             (1.64)                                                                             (1.84)                                                                             (2.5)                                                                             (1.0)                          __________________________________________________________________________     .sup.1 Control Gum was LifeSavers Grape Flavored Bubble Gum.                  .sup.2 Experimental Gum was the 2.5% TCP added to the control gum.            .sup.3 mean (std dev); n = 12 to 14                                           .sup.4 Means of the control and experimental groups are significantly         different (p < 0.05).                                                          Ca!.sub.F = free Ca concentration (mmol/L) measured by Ca electrode;          Ca.sub.T ! and  P.sub.T ! = total Ca and P concentrations measured by        spectrophotometric methods;                                                   pIAP =log(IAP) where IAP is ion activity product of hydroxyapatite.      

Effect of Gum Composition on Calcium and Phosphate ion Release

Two types of gums were tested as components of the invention: neutral pHand acidic pH gums. An example of an acidic pH gum tested wasLifeSavers® Grape bubble gum, as disclosed above in Table I. A neutralpH gum tested was LifeSavers® Peppermint gum, in experiments performedas described above to produce the data comprising Table I.

The results of experiments with neutral pH gums are shown in Table III.The data in Table III show that calcium and phosphate ions are notefficiently released from a neutral pH gum (LifeSavers® Peppermint gum).In fact, none of the calcium phosphate compounds tested (with theexception of MCPM) was capable of releasing calcium or phosphate ionsunless the gum has an acidic pH and produces an acid pH in saliva (i.e.,pH less than 7.0; compare the data in Table I with the data in TableIII).

                  TABLE III                                                       ______________________________________                                        Release of Ca.sup.++  Ions Into Saliva from pH Neutral                        Gums Containing Calcium Phosphate Additives                                                Calcium Concentration.sup.1, mmol/L                              Additive       0-2 min.   14-16 min                                           ______________________________________                                        Control        1.11 ± 0.11                                                                           0.90 ± 0.07                                      5% (TTCP/DCPA) 0.82 ± 0.03                                                                           0.82 ± 0.02                                      5% α-TCP 0.72 ± 0.03                                                                           0.77 ± 0.03                                      5% TTCP        1.03 ± 0.14                                                                           1.05 ± 0.22                                      2% MCPM        3.74 ± 0.68                                                                           1.15 ± 0.20                                      5% MCPM        6.56 ± 0.84                                                                           0.92 ± 0.23                                      ______________________________________                                         .sup.1 mean ± s.d. (n = 3)                                            

In other experiments, neutral gums were used to release anticariouscalcium phosphate agents under certain conditions. This was achieved byadding separate calcium-containing and phosphate-containing compounds tothe gum. Calcium-containing compounds used as separatecalcium-containing additives were the calcium salts of gluconic acid,lactic acid, fumaric acid, and glycerophosphoric acid. Results usingthese compounds are shown in Table IV. In these experiments it was foundthat the solubilities of these calcium-containing compounds areessentially independent of pH (in contrast to calcium phosphatecompounds, which require acidic pH). Calcium carbonate and the calciumsalts of two commonly used food acids, citric acid and tartaric acid,were too insoluble to produce effective release (Table IV). Theanticaries effects derived from the calcium compounds were significantlyaugmented by adding an equimolar mixture of Na₂ HPO₄ and NaH₂ PO₄ (tomaintain pH at 7). This caused a significant release of phosphate ionsinto saliva. The data further showed that the combination of a calciumsource (e.g., calcium glycerophosphate) and a phosphate source (e.g.,sodium phosphate) in a gum resulted in the desired release of bothcalcium and phosphate ions. It was also found that a sparingly-solublecalcium source (such as calcium glycerophosphate) could be used withMCPM (which served as a source for both calcium and phosphate ions).

                  TABLE IV                                                        ______________________________________                                        Release of Calcium and Phosphate Ions Into Saliva from pH                     Neutral Gums Containing Separate Calcium and Phosphate Additives                               Concentration.sup.1, mmol/L                                  Additive           0-2 min    14-16 min                                       ______________________________________                                        Control         Ca!    1.11 ± 0.11                                                                           0.90 ± 0.07                              5% Ca lactate   Ca!    10.3 ± 2.20                                                                           2.48 ± 0.20                              5% Ca gluconate                                                                               Ca!    4.85 ± 1.32                                                                           1.87 ± 0.27                              5% Ca citrate   Ca!    1.20 ± 0.12                                                                           1.30 ± 0.13                              5% Ca glycerophosphate                                                                        Ca!    8.84 ± 1.45                                                                           2.14 ± 0.71                                              P!     3.59 ± 1.33                                                                           3.51 ± 0.73                              3% Ca glycerophosphate +                                                                      Ca!    5.80 ± 0.54                                                                           1.21 ± 0.09                              2% MCPM         P!     12.8 ± 1.70                                                                           6.63 ± 1.70                              2% Na phosphate                                                                               Ca!    0.55 ± 0.07                                                                           0.76 ± 0.14                                              P!     20.3 ± 0.26                                                                           4.15 ± 0.70                              5% Ca carbonate                                                                               Ca!    0.80 ± 0.00                                                                           0.93 ± 0.07                              ______________________________________                                         .sup.1 mean ± s.d. (n = 3)                                            

Preparation of calcium phosphate-containing remineralizing toothpastes

One embodiment of the remineralizing toothpastes of the inventioncomprise a calcium-containing component and a phosphate-containingcomponent, stored in separate containers to prevent prematuredevelopment of hydroxyapatite in the presence of the wet components ofthe toothpaste. In a first example, a calcium phosphate-containingtoothpaste is prepared as described in Table V. In this example, thecalcium source is calcium glycerophosphate and the phosphate cource ismonohydrogenphosphate heptahydrate and sodium dihydrogen phosphate. Thephosphate-containing component also advantageously contains sodiumfluoride as a fluoride source. A second example of a calciumphosphate-containing toothpaste is shown in Table VI. In this example,the calcium source is calcium gluconate and the phosphate source ismonocalcium phosphate monohydrate. The phosphate-containing componentalso advantageously contains sodium monofluorophosphate as a fluoridesource instead of sodium fluoride, since the latter fluoride source willreact with monocalcium phosphate monohydrate to form calcium fluorideand fluoroapatite (thus preventing the release of either phosphate orfluoride in the toothpaste during application). In both examples, thetoothpastes are forumulated so that the calcium source component and thephosphate source component are used in equal amounts (by weight) duringapplication, using established packaging means and other methods knownin the dental arts.

                  TABLE V                                                         ______________________________________                                        Remineralzing Toothpaste Example 1                                            Component          Paste A    Paste B                                         ______________________________________                                        calcium glycerophosphate                                                                         4.2      g     0                                           sodium monohydrogen phosphate                                                                    0              2.68   g                                    heptahydrate                                                                  sodium dihydrogen phosphate dihydrate                                                            0              1.56   g                                    sodium fluoride    0              0.48   g                                    sorbitol (70% solution)                                                                          15       g     15     g                                    silica             35       g     35     g                                    glycerine          15       g     15     g                                    sodium carboxymethyl cellulose                                                                   1        g     1      g                                    sodium η-lauryl sarcosinate                                                                  1        g     1      g                                    water, coloring, flavoring                                                                       q.s. to 100                                                                            g     q.s. to 100                                                                          g                                    ______________________________________                                    

                  TABLE VI                                                        ______________________________________                                        Remineralzing Toothpaste Example 2                                            Component          Paste A    Paste B                                         ______________________________________                                        calcium gluconate  8.96     g     0                                           monocalcium phosphate monohydrate                                                                0              2.52   g                                    sodium monofluorophosphate                                                                       0              1.67   g                                    sorbitol (70% solution)                                                                          15       g     15     g                                    silica             35       g     35     g                                    glycerine          15       g     15     g                                    sodium carboxymethyl cellulose                                                                   1        g     1      g                                    sodium η-lauryl sarcosinate                                                                  1        g     1      g                                    water, coloring, flavoring                                                                       q.s. to 100                                                                            g     q.s. to 100                                                                          g                                    ______________________________________                                    

Another embodiment of the remineralizing toothpastes of the presentinvention comprises a dry powder containing a calcium phosphate source.Preferred calcium phosphate compositions are tetracalcium phosphate,α-tricalcium phosphate and monocalcium phosphate. Upon use the powdercan be mixed with a liquid, i.e., water, to form a paste. The paste isthen applied to the teeth.

Preparation of calcium phosphate-containing gels

All remineralizing gels comprise a calcium-containing component and aphosphate-containing component, stored in separate containers to preventpremature development of hydroxyapatite in the presence of the wetcomponents of the gel. In a first example, the formulation of which isshown in Table VII, these components comprise a liquid component and adry (powder) component. In this embodiment, the liquid is combined withthe powder immediately prior to use to obtain a smooth gel, which isthen applied to the areas in which reminieralization is desired(including, for example, sensitive root surfaces and caries lesions onthe chewing surfaces of teeth). In the practice of this aspect of theinvention, it is anticipated that an amount of about 10 g of the geldescribed herein will be advantageously applied for remineralizingpurposes, and the example set out in Table VII is formulated therefore.

                  TABLE VII                                                       ______________________________________                                        Remineralizing Gel Example 1                                                  Components       Dry Powder      Liquid                                       ______________________________________                                        α-tricalcium phosphate                                                                   0.8     g       0                                            sodium carboxymethyl cellulose                                                                 0.35    g       0                                            sodium fluoride  0.024   g       0                                            sorbitol (70% solution)                                                                        0               1.5   g                                      water            0               7.326 g                                      ______________________________________                                    

In a second example, the formulation of which is shown in Table VIII,the formulation comprises an equal amount of two gels, one comprising acalcium source and the other comprising a phosphate source, which aremixed immediately prior to use to produce a homogeneous gel.

                  TABLE VIII                                                      ______________________________________                                        Remineralizing Gel Example 2                                                  Component          Gel 1      Gel 2                                           ______________________________________                                        calcium glycerophosphate                                                                         8.4      g     0                                           sodium monohydrogen phosphate                                                                    0              5.36   g                                    heptahydrate                                                                  sodium dihydrogen phosphate dihydrate                                                            0              3.12   g                                    sodium fluoride    0              0.95   g                                    sorbitol (70% solution)                                                                          15       g     15     g                                    sodium carboxymethyl cellulose                                                                   6        g     6      g                                    water, flavoring, coloring                                                                       q.s. to 100                                                                            g     q.s. to 100                                                                          g                                    ______________________________________                                    

Preparation of calcium phosphate-containing candies

Both sugar-free candies (Table IX) and sugar-containing candies (TableX) are described. In this aspect of the invention, calcium and phosphatesources can be combined in the same phase without concern of prematurehydroxyapatite-producing reactions between the two compounds, sincethere is essentially no free water in such candies.

                  TABLE IX                                                        ______________________________________                                        Remineralizing Sugar-Free Candy Example                                       Component                Amount                                               ______________________________________                                        calcium glycerophosphate 8.4      g                                           sodium monohydrogen phosphate heptahydrate                                                             5.36     g                                           sodium dihydrogen phosphate dihydrate                                                                  3.12     g                                           sorbitol, flavoring, coloring                                                                          q.s. to 100                                                                            g                                           ______________________________________                                    

                  TABLE X                                                         ______________________________________                                        Remineralizing Candy Example                                                  Component              Amount                                                 ______________________________________                                        α-tricalcium phosphate                                                                         8        g                                             sugar, corn syrup, flavoring, coloring                                                               q.s. to 100                                                                            g                                             ______________________________________                                    

It should be understood that the foregoing disclosure emphasizes certainspecific embodiments of the invention and that all modifications oralternatives equivalent thereto are within the spirit and scope of theinvention as set forth herein.

We claim:
 1. A calcium phosphate-containing composition comprising achewing gum, wherein the chewing gum is an acidic chewing gum, andwherein the chewing gum further comprises a sparingly-soluble calciumphosphate salt selected from the group consisting of α-tricalciumphosphate, tetracalcium phosphate, dicalcium phosphate anhydrous,dicalcium phosphate dihydrate and octacalcium phosphate.
 2. The chewinggum of claim 1, wherein the calcium phosphate salt comprises from 0.5 to10 weight percent of the chewing gum.
 3. The chewing gum of claim 1,wherein the calcium phosphate salt comprises from 1 to 5 weight percentof the chewing gum.
 4. The chewing gum of claim 1, wherein the calciumphosphate salt comprising the chewing gum has a particle size of lessthan 50 μm.
 5. The chewing gum of claim 4, wherein the calcium phosphatesalt comprising the chewing gum has a particle size of 1 to 20 μm.
 6. Acalcium phosphate containing composition comprising an acidic chewinggum, wherein the chewing gum comprises a calcium compound and aphosphate salt, the composition being capable of releasing calcium andphosphate ions into saliva.
 7. The chewing gum of claim 6 wherein thechewing gum is a neutral gum.
 8. A chewing gum according to claim 6,wherein the calcium compound is selected from the group consisting ofcalcium acetate and calcium chloride.
 9. A chewing gum according toclaim 6, wherein the calcium compound is a sparingly-soluble calciumcompound.
 10. A chewing gum according to claim 9, wherein thesparingly-soluble calcium compound is selected from the group consistingof the calcium salts of glycerophosphate, lactate, gluconate, andfumarate.
 11. A chewing gum according to claim 6, wherein the calciumcompound comprises from 0.5 to 10 weight percent of the chewing gum. 12.The chewing gum of claim 6, wherein the calcium compound comprises from1 to 5 weight percent of the chewing gum.
 13. The chewing gum of claim6, wherein the calcium compound comprising the chewing gum has aparticle size of less than 50 μm.
 14. The chewing gum of claim 6,wherein the calcium compound comprising the chewing gum has a particlesize of 1 to 20 μm.
 15. The chewing gum of claim 6, wherein thephosphate salt is selected from the group consisting of Na₂ HPO₄, NaH₂PO₄, and Ca(H₂ PO₄)₂.H₂ O.
 16. The chewing gum of claim 6, wherein thephosphate salt comprises 0.5 to 10 weigh percent.
 17. The chewing gum ofclaim 6, wherein the phosphate salt comprising the chewing gum has aparticle size of less than 50 μm.
 18. The chewing gum of claim 17,wherein the phosphate salt comprising the chewing gum has a particlesize of 1 to 20 μm.
 19. A method of remineralizing a dental lesion in ahuman, the method comprising the step of having the human chew a chewinggum according to claim
 1. 20. A method of remineralizing a dental lesionin a human, the method comprising the step of having the human chew achewing gum according to claim
 6. 21. A method of remineralizing dentalplaque in a human, the method comprising the step of having the humanchew a chewing gum according to claim
 1. 22. A method of remineralizingdental plaque in a human, the method comprising the step of having thehuman chew a chewing gum according to claim
 6. 23. A method of reducingcariogenic challenge to human teeth, the method comprising the step ofhaving the human chew a chewing gum according to claim
 1. 24. A methodof reducing cariogenic challenge to human teeth, the method comprisingthe step of having the human chew a chewing gum according to claim 6.25. A method of desensitizing hypersensitive human teeth, the methodcomprising the step of having the human chew a chewing gum according toclaim
 1. 26. A method of desensitizing hypersensitive human teeth, themethod comprising the step of having the human chew a chewing gumaccording to claim 6.